Rashid Faizan, Ahmad Saeed, Irudayaraj Joseph Maria Kumar
Biomedical Research Center in Mills Breast Cancer Institute, Carle Foundation Hospital, Urbana, IL 61801, USA.
Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Toxics. 2020 Aug 28;8(3):64. doi: 10.3390/toxics8030064.
Perfluorooctanoic acid (PFOA) has been implicated in various toxicities including neurotoxicity, genotoxicity, nephrotoxicity, epigenetic toxicity, immunotoxicity, reproductive toxicity, and hepatotoxicity. However, information on the accumulation of PFOA in the intestine and its toxic effects on intestinal epigenetics and tight junction (TJ) genes is sparse. CD1 mice were dosed with PFOA (1, 5, 10, or 20 mg/kg/day) for 10 days, and its accumulation and induced alterations in the expression of epigenetic and tight junction genes in the small intestine and colon were evaluated using LC-MS and qPCR techniques. PFOA reduced the expression levels of DNA methyltransferases () primarily in the small intestine whereas, in the colon, a decrease was observed only at high concentrations. Moreover, ten-eleven translocation genes ( and ) expression was dysregulated in the small intestine, whereas in the colon remained unaffected. The tight junction genes Claudins (), Occludin (), and Tight Junction Protein () were also heavily altered in the small intestine. TJs responded differently across the gut, in proportion to PFOA dosing. Our study reveals that PFOA triggers DNA methylation changes and alters the expression of genes essential for maintaining the physical barrier of intestine, with more profound effects in the small intestine compared to the colon.
全氟辛酸（PFOA）与多种毒性有关，包括神经毒性、遗传毒性、肾毒性、表观遗传毒性、免疫毒性、生殖毒性和肝毒性。然而，关于PFOA在肠道中的积累及其对肠道表观遗传学和紧密连接（TJ）基因的毒性作用的信息却很少。给CD1小鼠连续10天给予PFOA（1、5、10或20毫克/千克/天），并使用液相色谱-质谱联用（LC-MS）和定量聚合酶链反应（qPCR）技术评估其在小肠和结肠中的积累情况以及对表观遗传和紧密连接基因表达的诱导变化。PFOA主要降低了小肠中DNA甲基转移酶的表达水平，而在结肠中，仅在高浓度下观察到表达下降。此外，在小肠中，十一转位基因（TET1和TET2）的表达失调，而在结肠中，TET1不受影响。紧密连接基因Claudins（CLDN1、CLDN3和CLDN4）、闭合蛋白（OCLN）和紧密连接蛋白1（ZO-1）在小肠中也发生了显著变化。紧密连接在整个肠道中的反应不同，与PFOA给药剂量成比例。我们的研究表明，PFOA引发DNA甲基化变化，并改变维持肠道物理屏障所必需的基因表达，与结肠相比，对小肠的影响更为深远。
